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Y Ohmiya

Publications and source records attributed to Y Ohmiya.

53 records · Page 3Linked to original sources
PubMed1983

N-oxidation of N,N-dimethylaniline in the rabbit and rat lung.

We have reported previously that chlorpromazine (CPZ) and imipramine (IMP) are metabolized via N-oxidation by the rat lung, while they are not appreciably metabolized by the rabbit lung. Indeed, marked species differences exist in the pulmonary N-oxidation of these pneumophilic drugs. In the present studies, the isolated, ventilated and perfused lung (IPL) preparations as well as in vitro preparations of the rabbit and rat lungs were used to examine the pulmonary disposition of [14C]-N,N-dimethylaniline (DMA) which has been used frequently as a substrate for N-oxidation. Although the IPLs of both species were active in DMA N-oxidation, the rabbit lung was more active in DMA N-oxidation than the rat lung on the basis of per g lung. The gradual decline in radiolabel concentration in the perfusate was more marked in the rat than in the rabbit IPL. This decline was not due to the drug accumulation in the lung, but to its volatility. There was no dose dependency in the tissue/medium DMA concentration ratios (approximately 1.60), indicating uptake by simple diffusion and low affinity for the lung tissue. In vitro lung preparations showed higher DMA N-oxidase activity in the rabbit than in the rat, regardless of whether whole homogenate, post-mitochondrial supernatant fraction or microsomal fraction was used, or how the activities were expressed (per mg protein or per g tissue). These results suggest that, although DMA is not highly concentrated in the lung, it is N-oxidized by the lung and that DMA N-oxidase is different from CPZ or IMP N-oxidase reported previously.

Aniline Compounds↗
PubMed1981

The isolated perfused lung--a critical evaluation.

Recent refinement and application of the technique of perfusing isolated intact lung preparations from suitable experimental animal has enhanced our knowledge of the non-respiratory functions of the lung. The technique consists of perfusion with whole blood or constituted media via pulmonary artery or artificially ventilated lungs. Such preparations have been known to be especially useful for studies of uptake, metabolism and disposition of exogenous and endogenous substances. Recent advances in unilateral, split-lung perfusion in which left and right lungs are unilaterally perfused simultaneously have enabled investigators to maintain paired controls during perfusion. Such techniques are useful in the study of the interactions of endogenous and exogenous chemicals in the lung tissue. Differences between subcellular or lung slice preparations and intact lung perfusion are to be expected on the basis of distorting natural vascular and extra-vascular barriers in the case of in vitro preparations. Areas in which perfused lungs have not been extensively used include uptake and disposition of gases, solvents and vapors, effects of toxic chemicals on respiratory and non-respiratory functions of the lung and alteration of pulmonary mechanisms and hemodynamics in the presence of interacting chemical or physical stimuli. With suitable modifications, application of isolated perfused lung preparations for these investigations should be technically feasible in the future.

Animals↗
PubMed1981

Pulmonary metabolism of imipramine in the rat and rabbit. Comparison with hepatic metabolism.

The pulmonary metabolism of imipramine (IMP) was studied, using lung tissue preparations of rats and rabbits, and compared with the metabolism by liver tissue. The postmitochondrial (9,000 g) supernatant fraction was used as the enzyme source, and the differential extraction method was employed to separate and quantitate the metabolites of IMP. The IMP-metabolizing activity of rat lung was found to be significantly higher than that of rabbit lung. The major metabolite produced by rat lung was identified as IMP-N-oxide (IMP-NO). Inclusion of beta-dimethylaminoethyl-diphenyl valerate (SKF-525A; l mM) and depletion of Mg2+ did not inhibit, but slightly increased the N-oxidation of IMP by the lung preparations, whereas piperonyl butoxide (l mM) and Hg2+ (0.1 mM) had little or no effect. The liver/lung ratio of the IMP-metabolizing activity was found to be variable depending on the substrate concentrations used, indicating the unreliability of such ratios as indices of the relative contribution of the lung to the metabolism of a drug. These results suggest that a marked species variation exists with respect to the pulmonary of IMP, that the principal product in rat lung is IMP-NO, and that this biotransformation is catalyzed by a noncytochrome P-450 pathway.

Animals↗
PubMed1978

Interaction of benzyl alcohol with human erythrocytes.

The uptake of benzyl alcohol by human erythrocytes and its binding to cell membranes were examined in vitro relation to its hemolytic actions. The hemolysis induced by benzyl alcohol was found to be time-, dose- and temperature-dependent. Little or no hemolysis was observed until the concentration of benzyl alcohol increased over a certain level. Radiotracer studies revealed that in contrast to the rapid cellular uptake which was independent of temperature, the binding of benzyl alcohol to membranes increased gradually with time and was dependent mainly on the temperature. The critical hemolytic levels of the alcohol bound to membranes were estimated to be about 500 nmoles/mg protein. The results obtained herein suggest that the process of hemolysis induced by benzyl alcohol depends on the binding of the alcohol to erythrocyte membranes.

Benzyl Alcohols↗
PubMed1978

Potentiation of toluene toxicity by hepatic enzyme inhibition in mice.

The toxicity of toluene was evaluated in male mice by the narcotic effects and lethality. The i.p. LD50 of toluene for male mice was calculated to be 1.15g/kg according to the method of Weil. Pretreatment with phenobarbital, produced a marked decrease in the number of sleep induced by a test dose (0.96 g/kg i.p.) of toluene. By contrast, pretreatment with a variety of hepatic enzyme inhibitors such as CCl4, SKF 525A, pyrazole and cyanamide was found to produce an increase in the number of sleep and death, accompanied with the prolongation of sleeping time. The present results suggest that the toxicity of toluene is enhanced by the inhibition of any step of metabolism.

Animals↗
PubMed1978

Protein-mediated transfer of DDT to adipose tissue.

The in vitro transfer of DDT through various media to rat adipose tissue was examined. About 15% of DDT was transferred through Krebs-Ringer solution to the tissue slices after 2-hr incubation at 37 degrees C. The addition of albumin accelerated the transfer of DDT proportionally to the concentrations up to 1.0%. Hemoglobin and gamma-globulin showed a lesser accelerating activity, but protamine, trypsin and pepsin showed little or no effect. When the Krebs-Ringer solution was replaced by triglyceride suspensions, only a small amount of DDT was taken up by the adipose tissue. Ffflux experiments revealed that the adipose tissue scarcely released DDT into albumin solution or triglyceride suspensions. The results suggest that lipid may play an important role as a storage site of DDT and that albumin may behave as a carrier system.

Adipose Tissue↗
PubMed1977

Effect of methylmercury on the ethanol elimination from the blood and the activity of alcohol dehydrogenase.

In an attempt to assess the effects of methylmercury on ethanol metabolism, Sprague-Dawley rats were treated with a daily dose (10 mg/kg i.p.) of methylmercuric chloride for 2 consecutive days and given a test dose (0.4 g/kgi.v.) of ethanol 24 hr after the last treatment. Blood ethanol levels were measured using gaschromatography by the direct introduction of blood samples into the sample vaporizing apparatus attached to the chromatograph. While treatment with methylmercury elicited a slight retardation in the ethanol elimination from the blood during 30 to 90 min, methylmercury did not essentially alter ethanol metabolism. There was no significant change in hepatic alcohol dehydrogenase activity of methylmercury-treated rats. By contrast, the activity of alcohol dehydrogenase purified from liver or yeast was remarkably inhibited by methyl-mercury and the type of inhibition proved to be non-competitive. Moreover, the inhibited activity was reactivated easily by sulfhydryl agents. From these results, it is conceivable that methylmercury has little influence on ethanol metabolism in vivo because of its non-specific binding with sulfhydryl groups in the organism.

Alcohol Oxidoreductases↗
PubMed1977

Effect of starvation on excretion, distribution and metabolism of DDT in mice.

Effect of starvation on tissue radioactivity of 14C-DDT was examined in mice 8 days after its single injection. Animals were completely fasted and given barium sulfate by gastric intubation for the last 3 days. The findings obtained from starved mice were as follows: 1) loss of body weight, 2) decrease in organ weight of epedidymal fat and liver, 3) reduction in lipid content of whole body as well as of epididymal fat, 4) a marked elevation of DDT levels in tissues except muscle, and 5) occasional neurotoxidc signs characterized by tremors and convulsions. Excretion of DDT-related metabolites was not changed by starvation. Analysis of metabolic producets of 14C-DDT using thin-layer radiochromatography revealed that there was little or no significant difference between control and starved mice in the metabolic pattern of DDT-related compounds in the tissues and excreta. It was assumed the DDT-ingested animals with dietary energy restriction had a subsequent risk of toxicity resulted from redistribution of DDT, but not from alteration in excretion or metabolism.

Adipose Tissue↗
PubMedDate not supplied

Bovine serum albumin displays luciferase-like activity in presence of luciferyl adenylate: insights on the origin of protoluciferase activity and bioluminescence colours.

Luciferyl adenylate, the key intermediate in beetle bioluminescence, is produced through adenylation of d-luciferin by beetle luciferases and also by mealworm luciferase-like enzymes which produce a weak red chemiluminescence. However, luciferyl adenylate is only weakly chemiluminescent in water at physiological pH and it is unclear how efficient bioluminescence evolved from its weak chemiluminescent properties. We found that bovine serum albumin (BSA) and neutral detergents enhance luciferyl adenylate chemiluminescence by three orders of magnitude, simulating the mealworm luciferase-like enzyme chemiluminescence properties. These results suggest that the beetle protoluciferase activity arose as an enhanced luciferyl adenylate chemiluminescence in the protein environment of the ancestral AMP-ligase. The predominance of luciferyl adenylate chemiluminescence in the red region under most conditions suggests that red luminescence is a more primitive condition that characterized the original stages of protobioluminescence, whereas yellow-green bioluminescence may have evolved later through the development of a more structured and hydrophobic active site.

Adenosine Monophosphate↗
PubMedDate not supplied

Uptake and metabolism of chlorpromazine by rat and rabbit lungs.

Isolated perfused rat lung and in vitro rat and rabbit lung preparations were used to study the pulmonary uptake and metabolism of chlorpromazine (CPZ). Rat lungs were artificially ventilated and perfused via pulmonary artery with recirculating perfusate containing 1.7--180 microM 14C-CPZ. In the perfusate, 14C-CPZ-derived radioactivity declined rapidly, representing maximal pulmonary uptake at 5 min. Thereafter, the total radioactivity in the perfusate increased steadily. During the latter phase, the appearance of CPZ metabolites in the perfusate more than offset the continued decline in CPZ, suggesting metabolism of previously sequestered CPZ and a net, steady efflux of metabolites from the lung. Increasing concentration of metabolites paralleled the increase in total 14C in the perfusate. The principal metabolite was identified as CPZ-N-oxide. Biotransformation of CPZ by the perfused rat lung was temperature-sensitive and dependent on substrate concentration. Substrate saturation was apparent at 120 microM CPZ in the perfusate. In vitro incubation of 14C-CPZ with 9000g supernatant fractions of rat and rabbit lungs revealed that CPZ-metabolizing activity of rat lungs is far greater than that of rabbit lungs. In accordance with the perfusion studies, the principal pathway was N-oxidation of CPZ in the rat lung incubations. Although quantitatively much less significant, CPZ was metabolized in rabbit lung incubations, via demethylation. SKF 525-A did not inhibit CPZ metabolism by perfused or in vitro rat lung preparations, but selectively enhanced N-oxidation of CPZ. Piperonyl butoxide was without any effect. Metabolism of CPZ by rabbit lung incubations was inhibited by SKF 525-A and piperonyl butoxide. These results suggest that CPZ is metabolized by the rat lungs principally via N-oxidation by a pathway not involving cytochrome P-450; the resultant metabolite, CPZ-NO, is released into the circulation, indicating significantly lower affinity for the lung tissue than the parent compounds.

Animals↗
PubMedDate not supplied

Effect of chlorphentermine pretreatment on chlorphentermine uptake by isolated perfused rat lung.

Chlorphentermine (CP), an anorectic agent currently in use, is known to be highly accumulated in the lung, causes pulmonary phospholipidosis, and has been suspected of causing pulmonary hypertension. These studies were undertaken to characterize the uptake and accumulation processes and to examine the effect of subacute CP treatment on the uptake kinetics of CP in the rat lung. Animals were treated po with a saline solution of CP (50 mg/kg/day) for 7 days and the controls received the vehicle only. Artificially ventilated isolated rat lung preparations were perfused with Krebs-Ringer bicarbonate buffer containing bovine serum albumin. CP was not metabolized by control or pretreated perfused lungs or by their 9000g supernatant or microsomal fractions. In recirculating perfusion experiments, steady-state uptake was reached after 20 min of perfusion with 0.17 mM CP. Lungs from rats treated with CP as described above accumulated CP to a greater extent and more rapidly than did lungs from control rats. Similarly, lungs from rats treated with CP accumulated significantly greater quantities of CP than control lungs during single-pass perfusion experiments. Whereas control lungs reached a steady state uptake within 7 min, lungs from CP treated animals failed to reach a steady-state uptake during a 10-min perfusion. The lungs from CP-treated rats retained most of the accumulated CP and exhibited a significantly increased half life of efflux in comparison to control rats. Removal of Na+ from the perfusion medium or the addition of harmaline significantly decreased the half-life of CP uptake and the amount of CP accumulated by the lung.

Absorption↗